The invention relates to a stereoselective process for the preparation of (R)-2-alkyl-3-phenyl-propionic acids and intermediate products obtained in the process steps.
In EP-A-0 678 503, xcex4-amino-xcex3-hydroxy-xcfx89-aryl-alkanecarboxamides are described which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing processes described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
In a new process, one starts from 2,7-dialkyl-8-aryl-4-octenoyl amides, whose double bond is simultaneously halogenated in the 5-position and hydroxylated in the 4-position under lactonization, then the halogen is substituted by azide, the lactone amidated and the azide then transferred to the amine group. The desired alkanecarboxamides are obtained with the new process both in high total yields and in a high degree of purity, and selectively pure diastereomers can be prepared. The halolactonization of process step a), the azidation of process step b), and the azide reduction of process step d) are described by P. Herold in the Journal of Organic Chemistry, Vol. 54 (1989), pages 1178-1185.
The 2,7-dialkyl-8-aryl-4-octenoyl amides may correspond for example to formula A, 
and especially to formula A1
wherein R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, R6 is C1-C6alkyl, R5 is C1-C6alkyl or C1-C6alkoxy, or R5 and R6 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or xe2x80x94CH2CH2Oxe2x80x94C(O)xe2x80x94 substituted if necessary with C1-C4alkyl, phenyl or benzyl.
The compounds of formulae A and Al are obtainable by reacting a compound of formula B 
as racemate or enantiomer, with a compound of formula C, as racemate or enantiomer, 
wherein R1 to R4, R5 and R6 are as defined above, Y is Cl, Br or I and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably Br and especially Cl.
The compounds of formula B are known from EP-A-0 678 503. The compounds of formula C may be prepared from amidation of the corresponding carbonic esters, amides, or halides. The formation of carboxamides from carbonic esters and amines in the presence of trialkyl aluminium or dialkyl aluminium halide, for example using trimethyl aluminium or dimethyl aluminium chloride, is described by S. M. Weinreb in Org. Synthesis, VI, page 49 (1988). The carbonic esters are obtainable by the reaction of trans-1,3-dihalogenpropene (for example, trans-1,3-dichlorepropene) with corresponding carbonic esters in the presence of strong bases, for example alkali metal amides.
A satisfactory solution for the stereoselective preparation of compounds of formula B has not yet been found, especially with regard to an industrial process. Surprisingly it has now been found that 2-alkyl-3-phenylpropionic acids can be stereoselectively prepared with high yields in only three process steps. When suitably substituted benzaldehydes are condensed with carbonic esters to form 2-alkyl-3-hydroxy-3-phenylpropionic acid esters, the desired diastereomers are obtainable in surprisingly high yields mostly as crystalline compounds which can be readily isolated. After conversion of the hydroxy group to a leaving group, 2-alkylcinnamic acid esters are then formed by elimination with strong bases with surprisingly high regioselectivity. The carboxylic acids obtained after saponification can in turn be surprisingly hydrogenated in the presence of homogeneous, asymmetric hydrogenation catalysts to form practically enantiomer-pure 2-alkyl-3-phenylpropionic acids. These acids can then be reduced in a manner known per se to form enantiomer-pure alcohols, from which the compounds of formula B are obtainable by halogenation.
The object of the invention is a process for the preparation of compounds of formula I, 
wherein R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, and R3 is C1-C6alkyl, comprising
(a) the reaction of a compound of formula II 
wherein R1 and R2 are as defined above, with a compound of formula III,
R3xe2x88x92CH2xe2x88x92COOR7xe2x80x83xe2x80x83(III), 
wherein R3 is as defined above, to form a compound of IV, 
wherein R7 is C1C12alkyl, C3-C8cycloalkyl, phenyl or benzyl,
(b) the isolation of the crystalline compound of formula IV, the conversion of the OH group to a leaving group, and the reaction of a compound containing a leaving group in the presence of a strong base to form a compound of formula V, 
(c) the hydrolysis of carbonic esters of formula V to form the carboxylic acid of formula VI, 
(d) the hydrogenation of the carboxylic acid of formula VI in the presence of hydrogen and catalytic quantities of a metal complex as asymmetric hydrogenation catalyst, comprising metals from the group of ruthenium, rhodium and iridium, to which the chiral bidentate ligands are bonded, to form a compound of formula I.
R1 and R2 may be a linear or branched alkyl and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.
R1 and R2 may be a linear or branched halogenalkyl and preferably comprise 1 to 4 C atoms, 1 or 2 C atoms being especially preferred. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
R1 and R2 may be a linear or branched alkoxy and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.
R1 and R2 may be a linear or branched alkoxyalkyl. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.
R1 and R2 may be linear or branched C1-C6alkoxy-C1-C6alkyloxy. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.
In a preferred embodiment, R1 is methoxy-C1-C4alkyloxy or ethoxy-C1-C4alkyloxy, and R2 is preferably methoxy or ethoxy. Quite especially preferred are compounds of formula I, wherein R1 is 1-methoxyprop-3-yloxy and R2 is methoxy.
R3 may be a linear or branched alkyl and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R3 in compounds of formula I is isopropyl.
Especially preferred are compounds of formula I wherein R1 is ethoxy-n-propoxy, R2 is methoxy and R3 is isopropyl.
R7 is preferably C1-C6alkyl, C1-C4alkyl being especially preferred; some examples are methyl, ethyl, n-propyl and n-butyl.
The starting compounds of formulae II and III used in process step a) are known or can be prepared in a manner similar to known processes. Compounds of formula II are described in EP-A 0 678 503. The reaction is advantageously carried out at low temperatures, for example 0-40xc2x0 C., in the presence of at least equivalent quantities of strong bases. The reaction is further expediently carried out in a solvent, ethers such as diethyl ether, tetrahydrofuran and dioxane being especially suitable. Suitable strong bases are in particular alkali metal alcoholates and secondary amides, such as lithium diisopropylamide.
The desired diastereomer of formula IV is surprisingly formed up to about 75%. The compounds of formula IV are surprisingly crystalline and can therefore be readily isolated without any substantial losses by means of extraction and crystallization.
The conversion of the OH group to a leaving group in reaction step b) is known per se. Reaction with carboxylic acids or sulfonic acids, or their anhydrides (acylation), is especially suitable. Some examples of carboxylic acids are formic acid, acetic acid, propionic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, methylsulfonic acid and trifluoromethylsulfonic acid. The use of acetic acid anhydride has proved especially successful. The elimination is expediently carried out in the presence of strong bases, alkali metal alcoholates such as potassium t-butylate being especially suitable. The presence of solvents such as ethers is expedient. The reaction is advantageously carried out at low temperatures, for example 0-40xc2x0 C. It is of advantage to conduct the elimination reaction directly in the reaction mixture for acylation. The elimination leads to the desired Z isomers with surprisingly high regioselectivity. These isomers are crystalline and can therefore be readily isolated without any substantial losses by means of extraction and crystallization. The yields are above 80%.
Hydrolysis of the ester of formula V to form the carboxylic acids of formula VI in process step c) is a generally known reaction. The hydrolysis may be carried out after isolation and purification of the compound of formula III. It is expedient to add water to the reaction mixture of process step b), to evaporate off the solvent and then to carry out alkaline or acidic hydrolysis. The carboxylic acids of formula VI are crystalline and can be readily isolated in yields of 80% or more.
The asymmetric hydrogenation in process step d) of xcex1,xcex2-unsaturated carboxylic acids with homogeneous, asymmetric hydrogenation catalysts is known per se and described for example by John M. Brown in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, 1999, pages 121 to 182. Especially effective are ruthenium and rhodium catalysts. Chiral ditertiary diphosphines whose phosphine groups in the 1,2, 1,3 or 1,4 position are bonded to a C2-C4carbon chain are often used as ligands. The skeletal structures of the chiral ditertiary diphosphines may be acyclic, monocyclic or polycyclic. The phosphine groups may be substituted with the same or with different, preferably the same, substituents selected from the group of C1-C8alkyl, C3-C8cycloalkyl, C6-C12aryl, and C6-C12aryl-C1-C4alkyl. Cycloalkyl and aryl may be unsubstituted or substituted with C1-C4alkyl, C1-C4alkoxy, C1-C4fluoroalkyl or C-C12secondary amino. Suitable phosphine groups are also phosphanyl, preferably five-member phosphanyl, which if necessary is substituted in one or both xcex1-positions with C1-C4alkyl or C1-C4alkoxy.
Some examples of chiral ditertiary diphosphines are (Rxe2x80x32P is for example diphenylphosphino or dicyclohexylphosphino, substituted if necessary) 1,2-Di-Rxe2x80x32P-propane, 2,3-Di-Rxe2x80x32P-butane, 1,2-Di-Rxe2x80x32P-norbornane or -norbornadiene, 1,2-Di-Rxe2x80x32P-cyclopentane, 1,2-Di-Rxe2x80x32P-N-methylpyrrolidine, 2,2xe2x80x3-Di-Rxe2x80x32P-biphenyl or -binaphthyl, 2,2xe2x80x3-Di-Rxe2x80x32P-6-methyl or -6,6xe2x80x2-dimethylbiphenyl, 2,2xe2x80x2-Di-Rxe2x80x32P-6-methoxy or -6,6xe2x80x2-dimethoxy-biphenyl, and 1-(xcex1-Rxe2x80x32P-ethyl)-2-Rxe2x80x32P-ferrocene.
Good optical yields are achieved using metal complexes of formula VII or VIIa,
[LMeYZ]xe2x80x83xe2x80x83(VII), 
[LMeY]+Exe2x88x92xe2x80x83xe2x80x83(VIIa), 
wherein
Me is rhodium;
Y stands for two olefins or one diene;
Z is Cl, Br or I;
Exe2x88x92 is the anion of an oxygen acid or a complex acid; and
L is a chiral ligand from the group of ditertiary diphosphines, in which the phosphine groups are bonded to a C2-C4 chain of the diphosphine backbone chain, and the diphosphine forms a five to seven-member ring together with the rhodium atom.
Where Y stands for two olefins, they may be C2-C12 olefins, C2-C6olefins being preferred and C2-C4olefins being especially preferred. Examples are propene, but-1-ene and especially ethylene. The diene may comprise 5 to 12 and preferably 5 to 8 C atoms and may be an acyclic, cyclic or polycyclic diene. The two olefin groups of the diene are preferably linked by one or two CH2 groups. Examples are 1,3-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4-cyclohexadiene, 1,4- or 1,5-heptadiene, 1,4- or 1,5-cycloheptadiene, 1,4- or 1,5-octadiene, 1,4- or 1,5-cyclooctadiene and norbornadiene. Y represents preferably two ethylene or 1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.
In formula VII, Z is preferably Cl or Br. Examples of E1 are ClO4xe2x88x92, CF3SO3xe2x88x92, CH3SO3xe2x88x92, HSO4xe2x88x92, BF4xe2x88x92, B(phenyl)4xe2x88x92, PF6xe2x88x92, SbCl6xe2x88x92, ASF6xe2x88x92 or SbF6xe2x88x92.
With known ligands for asymmetric catalysts, optical yields of up to about 80% ee can be achieved under optimized conditions. It was surprisingly found that new ligands with a ferrocenyl backbone are especially suitable for asymmetric hydrogenation of the compounds of formula VI. With these new ligands in the metal complexes of formulae VII and VIIa, optical yields of at least 95% ee can be achieved, which represents a substantial cost saving for manufacture on an industrial scale. In process step d), therefore, it is preferred to use metal complexes of formulae VII and VIIa which comprise ligands of formula VIII or VIIIa, 
wherein
n is 0 or an integer from 1 to 4 and Rxe2x80x2 represents the same or different substituents selected from the C1-C4alkyl, xe2x80x94CF3 and C1-C4alkoxy group; and
X1 and X2 are, independently of one another, secondary phosphino.
As an alkyl, Rxe2x80x2 may preferably comprise 1 to 2 C atoms. Linear alkyl is preferred. Examples of Rxe2x80x2 as an alkyl are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl. Methyl and ethyl are preferred, and methyl is especially preferred.
As an alkoxy, Rxe2x80x2 may preferably comprise 1 to 2 C atoms. Linear alkoxy is preferred. Examples of Rxe2x80x2 as an alkoxyl are methoxy, ethoxy, n- and i-propoxy, n-, i- and t-butoxy. Methoxy and ethoxy are preferred and methoxy is especially preferred.
The X1 and X2 groups may be different or preferably the same and correspond to formula PR8R9, wherein R8 and R9 are the same or different and represent branched C3-C8alkyl, C3-C8cycloalkyl, or unsubstituted or phenyl substituted with one to three C1-C4alkyl, C1-C4-alkoxy, or xe2x80x94CF3.
Special preference is for ligands of formulae VIII and VIIIa, wherein n is 0, and X1 and X2 are a PR8R9 group, wherein R8 and R9 in each case are cyclohexyl, phenyl or phenyl substituted with 1 or 2 methyl, methoxy or CF3.
The new ligands are prepared by means of reactions that are known per se or analogous to known reactions, such as those described in U.S. Pat. No. 5,371,256, U.S. Pat. No. 5,446,844 and U.S. Pat. No. 5,583,241. Ligands with other phosphine groups may be prepared in a manner analogous to the method described in the example.
The metal complexes used as catalysts may be added as separately prepared isolated compounds, or also formed in situ before the reaction and then mixed with the substrate to be hydrogenated. It may be advantageous in the reaction using isolated metal complexes to add additional ligands, or in the in situ preparation to use surplus ligands. The surplus may for example be up to 10 moles and preferably 0.001 to 5 moles, based on the metal complexes used for the preparation.
Process step d) may be carried out at low or elevated temperatures, for example at temperatures from xe2x88x9220 to 150xc2x0 C., preferably from xe2x88x9210 to 100xc2x0 C., temperatures of 10 to 80xc2x0 C. being especially preferred. The optical yields are generally better at low temperatures than at high temperatures.
The process according to the invention may be carried out at normal pressure or preferably under positive pressure. The pressure may for example range from 105 to 2xc3x97107 Pa (Pascal).
Catalysts are preferably used in quantities from 0.0001 to 10 mol-% based on the compound to be hydrogenated, the range 0.001 to 10 mol-% being especially preferred and the range 0.01 to 5 mol-% being preferred in particular.
The preparation of catalysts as well as process step d) and the other process steps may be carried out in the absence or the presence of an inert solvent, wherein one solvent or a mixture of solvents may be used. Suitable solvents are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, di- and tetrachloroethane), nitrites (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carbonic esters and lactones (ethyl or methyl acetate, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (dimethylamide, dimethylformamide), acyclic ureas (dimethylimidazoline), and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone) and alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether) and water. The solvents may be used alone or in a combination of at least two solvents.
The reaction may be carried out in the presence of co-catalysts, for example quaternary ammonium halogenides (tetrabutylammonium iodide) and/or in the presence of protonic acids, for example mineral acids.
Using the regioselective and enantioselective process according to the invention, the intermediate products of formula (B) may be prepared via all process steps in yields of at least 50% by weight, based on the compounds of formula II. The high total yields make the process suitable for industrial use.
A further object of the invention relates to the compounds (intermediates) of formula IX, 
wherein R1, R2 and R3 are as defined hereinbefore and X is the xe2x80x94COOH group.
The embodiments and preferences described hereinabove apply for R1, R2, and R3.
The following examples explain the invention in more detail.
A) Preparation of the Ligands